The present invention relates to new aromatic compounds, to a process for their preparation and to their use in human and veterinary medicine and in cosmetic compositions.
The compounds in accordance with the present invention exhibit an activity in the topical and systemic treatment of dermatologic diseases linked to a keratinization disorder (differentiation-poliferation) and dermatologic diseases (or others) having inflammatory and/or immunoallergic components and in the treatment of illnesses of the degeneration of conjunctive tissue as well as an anti-tumoral activity. Moreover, these compounds can be employed in the treatment of atophy, be it cutaneous or respiratory and in the treatment of rheumatoid psoriasis.
These compounds also possess good activity against the germs involved in acne.
Finally, the compounds of the present invention are usefully employed in the opthamology field and principally in the treatment of corneopathies.
The aromatic compounds of the present invention can be represented by the formula: ##STR2## wherein
n is 0 or 1,
(1) when n=1,
R' represents hydrogen or alkoxy having 1-4 carbon atoms,
R" represents hydrogen, OH, acyloxy having 1-4 carbon atoms, alkoxy having 1-4 carbon atoms or NH.sub.2,
or R' and R" taken together form an oxo (.dbd.O), methano (--CH.sub.2) or hydroxy imino (.dbd.N--OH) group,
R.sub.1 represents --CH.sub.2 OH or --COR.sub.10,
R.sub.10 represents hydrogen, --OR.sub.11 or ##STR3##
R.sub.11 represents hydrogen, linear or branched alkyl having 1 20 carbon atoms, monohydroxalkyl, polyhydroxyalkyl, aryl or aralkyl optionally substituted, the residue of a sugar or ##STR4## wherein p is 1, 2 or 3 and r' and r" represent hydrogen, lower alkyl, monohydroxyalkyl optionally interrupted by a heteroatom, polyhydroxyalkyl, aryl or benzyl optionally substituted, the residue of an amino acid or aminated sugar, or taken together form a heterocycle,
R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 represent hydrogen, --OH, linear or branched alkyl having 1-12 carbon atoms, cycoalkyl, cycloalkenyl, phenyl optionally substituted or a radical corresponding to one of the following formulas:
(i) --X--C.sub.6 H.sub.5,
(ii) --X--R.sub.12 or
(iii) --NHCOR.sub.13
wherein
X represents --O--, --S--, --SO--, --SO.sub.2 -- or --OCO--,
R.sub.12 represents alkyl or lower fluoroalkyl, and
R.sub.13 represents alkyl or phenyl, at least one of R.sub.2 to R.sub.6 being other than hydrogen,
R.sub.7, R.sub.8 and R.sub.9 represent hydrogen or methyl, R.sub.7 and R.sub.9 taken together being able to form, with the benzene ring, a naphthalene ring, with the exclusion of compounds of formula (I) wherein R.sub.7 is hydrogen or methyl when R4 represents methyl or OH, when R.sub.2, R.sub.3, R.sub.5 and R.sub.6 represent hydrogen or when R.sub.6 represent hydroxyl;
(2) when n.dbd.O
R' represents hydrogen,
R" represents OH, or
R' and R" taken together form an oxo (.dbd.O) radical,
R.sub.1 represents --CH.sub.2 OH, --CH.dbd.O or --COOR.sub.11 wherein R.sub.11 is hydrogen or lower alkyl,
R.sub.2 and R.sub.3 represent hydrogen or alkyl having 3-6 carbon atoms,
R.sub.5 represents
(i) either cycloalkyl or alkyl having 3-6 carbons atoms and in this case R.sub.4 represents lower alkyl, hydroxy or alkoxy, or
(ii) hydrogen and in this case R.sub.4 represents lower alkyl,
R.sub.6 represents hydrogen and
R.sub.7 represents hydrogen or methyl,
and the salts of said aromatic compounds as well as their optical and geometric isomers.
By lower alkyl is meant an alkyl radical having 1-6 carbon atoms.
Representative lower alkyl radicals and those having up to 20 carbon atoms include methyl, ethyl, isopropyl, butyl, tert.butyl, isooctyl, dodecyl, hexadecyl and octadecyl.
By monohydroxyalkyl is meant a radical having 2-6 carbon atoms and principally 2-hydroxyethyl, 2-hydroxypropyl or 2-hydroxy ethoxyethyl.
By polyhydroxyalkyl is meant a radical containing 3-6 carbon atoms and 2-5 hydroxyl groups such as 2,3-dihydroxypropyl, 1,3-dihydroxypropyl or the residue of pentaerythritol.
By aryl is meant phenyl optionally substituted by halogen, --OH, --NO.sub.2, lower alkyl, trifluoromethyl or a carboxylic acid function.
The preferred aralkyl radical is benzyl or phenethyl.
By residue of a sugar is meant a.residue derived, for example, from glucose, mannose, erythrose or galactose.
By residue of an amino acid is meant a residue derived, for example, from methionine or .alpha.- or .beta.-alanine.
Representative residues of aminated sugars include those derived from glucosamine, galactosamine or mannosamine.
By cycloalkyl is meant radicals having from 5-12 carbon atoms and principally cyclopentyl, cyclohexyl and adamantyl.
By cycloalkenyl is meant, preferably, cyclohexen-1-yl and cyclopenten-1-yl.
The preferred fluoroalkyl radicals are trifluoromethyl and pentafluoroethyl.
When the radicals r' and r" taken together from a heterocycle, the heterocycle is, preferably piperidino, piperazino, morpholino, pyrrolidino or 4-(2-hydroxyethyl) piperazino.
When the compounds according to the present invention are provided in the form of salts, they can be salts of an alkali or alkaline earth metal or even of zinc, or of an organic amine when they carry at least one free acid function, or of salts of a mineral organic acid, principally the hydrochloride, hydrobromide or citrate when they carry at least one amine function.
As a function of formula (I) above, the compounds of the present invention can be benzene derivatives or naphthalene derivatives of following formulas (II) and (III): ##STR5## wherein
R.sub.1 to R.sub.7, R' and R" have the same meanings given for those in formula (I) when n.dbd.O, ##STR6## wherein
R.sub.1 to R.sub.6, R' and R" have the same meanings given for those in formula (I) when n=1.
It will be noted that the compounds of formula (III) have good stability to light and oxygen.
Among the compounds of formula (II) those particularly preferred correspond to following formula (IV): ##STR7## wherein
R' represents hydrogen,
R" represents OH or
R' and R" taken together from an oxo (=0) radical,
R'.sub.1 represents --CH.sub.2 OH, --CH.dbd.O or --COOOR'.sub.11 wherein R'.sub.11 is hydrogen or lower alkyl,
R'.sub.2 and R'.sub.3 represent hydrogen or alkyl having 3-6 carbon atoms, and
R'.sub.5 represents either (i) cycloalkyl or alkyl having 3-6 carbon atoms and in this case R'.sub.4 represents lower alkyl, hydroxy or alkoxy, or (ii) hydrogen and in this case R'.sub.4 represents lower alkyl.
Among the compounds of formula (III) those particularly preferred correspond to following formulas (V) and (VI): ##STR8## wherein
R'.sub.10 represents --OR'.sub.11 or --NHR'.sub.11 wherein R'.sub.11 represents hydrogen or lower alkyl,
R'.sub.2 represents hydrogen or lower alkyl, and
R'.sub.4 represents lower alkyl, preferably isopropyl or tert.butyl, or cycloalkyl, preferably, cyclohexyl. ##STR9## wherein
R'.sub.10 represents --OR'.sub.11 or --NHR'.sub.11 wherein R'.sub.11 represents hydrogen or lower alkyl,
R".sub.2 and R'.sub.6 represent hydrogen or lower alkyl,
R'.sub.3 represents hydrogen, lower alkyl, phenyl or adamantyl, and
R'.sub.12 represents lower alkyl or phenyl.
Representative compounds of formula (I) in accordance with the present invention include the following:
(1) 6-(2,4-diisopropyl benzoyl) 2-methyl naphthalene carboxylate,
(2) 6-(2,4-diisopropyl benzoyl) naphthalene carboxylic acid,
(3) 6-(4-methoxy-2,3,6-trimethyl benzoyl)-2-methyl naphthalene carboxylate,
(4) 6-(4-methoxy -2,3,6-trimethyl benzoyl)-2-naphthalene carboxylic acid,
(5) 6-(4-tert.butyl benzoyl)-2-methyl naphthalene carboxylate,
(6) 6-(4-tert.butyl benzoyl)-2-naphthalene carboxylic acid,
(7) N-ethyl 6-(4-tert.butyl benzoyl)-2-naphthalene carboxamide,
(8) 6-(3-adamantyl-4-methoxy benzoyl)-2-naphthalene carboxylate,
(9) 6-(3-adamantyl-4-methoxy benzoyl)-2-naphthalene carboxylic acid,
(10) 6-(4-methoxy benzoyl)-2-methyl naphthalene carboxylate,
(11) 6-(4-cyclohexyl benzoyl)-2-methyl naphthalene.carboxylate,
(12) 6-(4-cyclohexyl benzoyl)-2-naphthalene carboxylic acid,
(13) 6-(4-methoxy-3-phenyl benzoyl)-2-methyl naphthalene carboxylate,
(14) 6-(4-methoxy-3-phenyl benzoyl)-2-naphthalene carboxylic acid,
(15) 6-(4-phenoxy benzoyl)-2-methyl naphthalene carboxylate,
(16) 6-[(2,4-diisopropyl phenyl) hydroxymethyl]-2-naphthalene carboxylic acid,
(17) 6-[(2,4-diisopropyl phenyl) hydroxymethyl]-2-naphthalene carbinol,
(18) 6-(2,4-diisopropyl benzyl-2naphthalene carboxylic acid,
(19) 4-(2,4-diisopropyl benzoyl) methyl benzoate,
(20) 4-(2,4-diisopropyl benzoyl) benzoic acid,
(21) 4-[(2,4-diisopropyl phenyl) hydroxymethyl]benzoic acid,
(22) 1-(2,4-diisopropyl phenyl)-1-(4-hydroxymethyl phenyl) methanol,
(23) 4-(2,4-diisopropyl benzoyl) benzaldehyde,
(24) 4-(2,4-diisopropyl benzoyl) .alpha.-methyl ethyl cinnamate,
(25) 4-(2,4-diisopropyl benzoyl) .alpha.-methyl cinnamic acid,
(26) [4-(3-adamantyl-4-methoxy phenyl) hydroxymethyl]methyl benzoate,
(27) 4-[(3-adamantyl-4-methoxyphenyl) hydroxymethyl] benzoic acid,
(28) 4-(3-adamantyl-4-methoxybenzoyl) benzoic acid,
(29) 4-(3-adamantyl-4-hydroxybenzoyl) benzoic acid,
(30) 4-(3-adamantyl-4-hydroxy benzoyl) methyl benzoate,
(31) 4-(3,5-di tert.butyl-4-hydroxy benzoyl) methyl benzoate and
(32) 4-(3,5-di tert.butyl-4-hydroxy benzoyl) benzoic acid.
The present invention also relates to a process for peparing the compounds of formula (I) defined above.
The compounds of formula (II) wherein R' and R" together form an oxo radical and n=0 are obtained in accordance with the following reaction scheme. ##STR10##
R.sub.11 =alkyl having 1-20 Carbon atoms.
The starting 4-alkoxycarbonyl benzoic acid is obtained by the oxidation of alkyl 4-formyl benzoate, preferably methyl 4-formyl benzoate which is a commercial product.
The corresponding acid chloride is prepared by the action of thionyl chloride in accordance with conventional methods for preparing acid chlorides.
The condensation reaction of the chloride of 4-alkoxy carbonyl benzoic acid (2) on the benzene derivative (3) is carried out under Friedel-Crafts reaction conditions, i.e. in the presence of anhydrous aluminum chloride in an organic solvent such as 1,2-dichloroethane at a temperature between 0.degree. and 25.degree. C. with stirring.
Starting with the ester (4) there is obtained by saponification the corresponding acid (5) which can then be transformed into the amide of formula (6( by reaction with an amine of the formula ##STR11## in the presence of N,N'-carbonyldiimidazole (CDI).
For certain meanings of R.sub.11 of formula (I), in particular when R.sub.11 represents a monohydroxy or polyhydroxy alkyl radical, it is preferable to prepare the acid (5) starting with the methyl ester (4) (R.sub.11 .dbd.--CH.sub.3) and then to esterify the resulting acid into the ester of the selected alcohol in accordance with known methods.
When in the compounds of formula (I) n=1, these compounds are obtained in accordance with the following reaction scheme: ##STR12##
The keto-acid (5) is reduced in the presence of lithium aluminum hydride to the corresponding diol (7) which is then oxidized in the presence of pyridinium chlorochromate (PCC) which leads to the ketoaldehyde (8). The latter, by the Wittig-Horner reaction with an alkyl phosphono acetate, substituted or not, leads, in the presence of sodium hydride in an organic solvent such as THF, to the unsaturated ester of formula (9).
The ester of formula (9) can than be transformed, as before, into the corresponding acid and then into the amide by reaction with an amine of the formula ##STR13##
The compounds of formula (II) wherein R'.dbd.H and R".dbd.OH are obtained starting with ketonic derivatives, by reduction with sodium borohydride in THF or methanol.
The compounds of formula (II) wherein R'=R"=H are obtained by the reduction with zinc of the ketonic derivatives, in acetic acid, in the presence of HCl.
These reduction reactions of the carbonyl must however be compatible with the nature of the various substituents (R.sub.2 to R.sub.7) as well as with the radical R.sub.1. It can be desirable to ensure optional protection, however, the reduction of the carbonyl creates no difficulty when R.sub.1 .dbd.--CO.sub.2 H.
The acyloxy derivatives of the compounds of formula (II) (R'.dbd.H and R".dbd.C.sub.1 -C.sub.4 acyloxy) are obtained by reacting an activated form of the acid such as an anhydride or acid chloride with a compound of formula (II) wherein R'.dbd.H and R".dbd.OH.
The alkoxy derivatives of the compounds of formula (II) (R'.dbd.H and R".dbd.C.sub.1 -C.sub.4 alkoxy) are also obtained starting with the compounds of formula (II) (R'.dbd.H and R".dbd.OH) in accordance with known methods.
For the preparation of the acyloxy and alkoxy derivatives it is preferable that the radical R.sub.1 is an ester, an acid or an amide function.
The compounds of formula (III) wherein R' and R" together form an oxo radical are obtained in acccordance with the following reaction scheme: ##STR14##
X=Br or Cl and R.sub.11 =C.sub.1 -C.sub.20 alkyl
The starting 6-alkoxy carbonyl-2naphthalene carboxylic acid (10) is obtained by the monosaponification reaction of 2,6 alkyl naphthalene dicarboxylate, preferably starting with 2,6 methyl naphthalene dicarboxylate which is a commercial product. The corresponding acid chloride (11) is prepared by reaction with thionyl chloride in accordance with conventional procedures for preparing acid chlorides.
The condensation reaction of the chloride of 6-alkoxy carbonyl-2-naphthalene carboxylic acid (11) can be effected either on the benzene derivative (12), under Friedel-Crafts conditions, or on the magnesium derivative of the halogeno benzene derivative (13).
The Friedel-Crafts reaction conditions are the same as those given above for the preparation of the compounds of formula (4). The preparation of the magnesium derivative of the halogeno benzene derivative (13) is effected in anhydrous THF at reflux and the condensation of the acid chloride is carried out at a temperature of about 0.degree. C. in the same solvent.
In accordance with the same methods as those described above for the compounds of formula (II) the other compounds of formula (III) can be prepared, i.e. compounds of formulas (15) and (16) as well as compounds of formula (III) wherein R' and R", taken together, are other than an oxo radical.
The present invention further relates to a medicine comprising the compounds of formula (I) as defined above.
These compounds exhibit excellent activity in the inhibition test of ornithine decarboxylase in nude rats, after induction, by "tape stripping", M. Bouclier, et al, Dermatologica 169, No. 4 (1984). This test is recognized as a measure of an antiproliferative activity.
These compounds are particularly appropriate for treating dermatologic ailments linked to a keratinization disorder (differentiation-proliferation) as well as dematologic diseases, or others, having an inflammatory and/or immunoallergic component, principally:
acne vulgaris, comedons or polymorphs, solar senile acne and medicinal or professional acne,
extensive and/or severe forms of psoriasis and other keratinization disorders, and principally ichtysoses and ichtysosis like conditions,
Darier malady,
palmo-plantar keratodermies,
leucophasies and leucophasie-like states, lichen plan,
all malignant or benign dermatologic proliferations, severe or extensive.
They are also active in the treatment of tumors, of rheumatoid psoriasis, cutaneous or respiratory atophies as well as in certain opthalmologic problems relating to corneopathies.
Thus, the present invention also relates to medicinal compositions containing at least one compound of formula (I), such as defined above, or one of its salts or one of its optical or geometric isomers.
The present invention thus relates to a new medicinal composition, intended principally for the treatment of the above-mentioned disorders, an effective amount of at least one compound of formula (I) and/or one of its salts and/or one of its optical or 9eometric isomers.
The compounds accordin9 to the present invention are generally administered at a daily dosage of about 2.mu.g/kg to 2mg/kg of body weight.
As the vehicle or carrier for these compositions any conventional vehicle can be employed, the active component being found either in the dissolved state, or in the dispersed state, in said vehicle.
The administration of the compounds of the present invention can be effected enterally, parenterally, topically or ocularly.
When administered enterally, the medicines can be provided in the form of tablets, gelules, lozenges, syrups, suspensions, solutions, powders, granules or emulsions.
When administered parenterally, the medicinal compositions can be provided in the form of solutions or suspensions for perfusion or injection.
When administered topically, the pharmaceutical compositions, based on the compounds according to the present invention, can be provided in the form of ointments, tinctures, creams, salves, powders, pads, impregnated tampons, solutions, lotions, gels, sprays or suspensions.
These compositions for topical administration can be provided under anhydrous form or in aqueous form according to clinical indications.
When administered ocularly, the is provided principally in the form of an eyewash.
The compositions for topical or ocular administration contain preferably from 0.0005 to about 5 percent by weight of at least one compound of formula (I) such as defined above relative to the total weight of the composition.
The compounds of formula (I), according to the present invention, are also useful in the cosmetic field, in particular in body and hair hygiene compositions and principally for the treatment of skin having acne tendencies, to improve the growth of hair, to combat hair loss, to combat against an only appearance of the skin or hair, in the prevention or treatment of the harmful effects of the sun or in the treatment of physiologically dry skin.
The present invention thus relates to a cosmetic composition containing, in a cosmetically acceptable vehicle, an effective amount of at least one compound of formula (I) or one of its salts and/or one of its isomers, this composition being provided principally in the form of a lotion, gel, cream, soap or shampoo.
The concentration of the compound of formula (I) in these cosmetic compositions is between 0.0005 and 2 percent by weight and, preferably, between 0.01 and 1 percent by weight based on the total weight of the composition.
The medicinal and cosmetic compositions according to the present invention can contain inert or even pharmacodynamic or cosmetically active additives and, principally: hydrating agents such as thiamorpholinone and its derivatives or urea; antiseborrheic or anti-acne agents such as S-carboxymethylcysteine, 5-benzylcysteamine, their salts and their derivatives, tioxolone or benzoyl peroxide; antibiotics such as erythromycin and its esters, neomycin, tetracyclines and 4,5-polymethylene-3-isothiazolones; agents promoting the growth of hair such as "Minoxidil" (2,4-diamino-6-piperidino-3-pyrimidine oxide) and its derivatives, Diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine-1,1-dioxide) and Phenytoin (5,5-diphenyl-2,4imidazolidine dione); steroidal and non-steriodal anti-inflammatory agents; carotenoids and, principally, .beta.-carotene; anti-psoriasic agents such as anthralin and its derivatives and 5,8,11,14-eicosatetraynoic and 5,8,11-eicosatriynoic acids, and their esters and amides.
The compositions according to the present invention can also include flavor improving agents, preservatives, stabilizers, humidity regulating agents, pH regulating agents, osmotic pressure modifying agents, emulsifiers, UV-A and UV-B filters, anti-oxidants such as .alpha.-tocopherol, butylhydroxyanisole or butylhydroxy toluene.